While the association of particular HLA Class II antigens with autoimmune diseases has been known for some time, the molecular basis for HLA-linked susceptibility is unknown. Whether the differential regulation of these susceptibility alleles also contributes to disease risk ia an important issue that has not been addressed. Quantitative differences in Class II molecules expressed on the cell surface can influence the intensity of the immune response, and in addition, promoter variation can alter the specificity of tissues in which these molecules might be aberrantly expressed. We hypothesize that allele-specific functional differences, resulting from nucleotide variations in the promoter regions of particular DRB alleles, may play a crucial role in altering the immune response and thus contribute to the association of specific HLA Class II alleles with autoimmune disease. We propose to determine the nucleotide sequence of regulatory regions from a number of disease-associated HLA-DRB alleles, and to test them functionally for allelic differences in relative promoter strength, binding of nuclear proteins, inducibility by particular cytokines, and tissue specificity. The demonstration of such promoter region allelic polymorphism sheds light on a critical step in the initiation of normal and abnormal immune responses, and has important implications for the triggering of autoimmune diseases.